Therapeutic patch

ABSTRACT

The invention relates to a topical patch comprising a therapeutic compound-impermeable backing layer, a self-adhesive matrix based on polysiloxanes and containing capsaicin or a therapeutic compound analogous to capsaicin, and a protective film to be removed before use, in which the matrix contains liquid microreservoirs based on an amphiphilic solvent, in which the therapeutic compound is present in completely dissolved form and the concentration of the therapeutic compound in the microreservoir droplets is below the saturation concentration. The invention furthermore relates to a process for its production and its use in the treatment of neuropathic pain.

BACKGROUND

Neuropathic pain is believed to result from sensitization reactions inthe peripheral and central nervous system. Such pain can occur as aresult of peripheral injuries, or as a result of systemic diseases suchas HIV, herpes zoster, syphilis, diabetes and autoimmune diseases.Neuropathic pain can be severe and is often debilitating, and effectivemethods for reducing neuropathic pain would ameliorate significantsuffering.

In U.S. Pat. No. 6,248,788 (Robbins et al.), a topical method oftreatment of neuropathic pain with capsaicin or substances analogous tocapsaicin is described. The Robbins et al. patent disclosed thattreatment of the affected body areas once or at most twice with a highlyconcentrated capsaicin preparation for a few hours eliminates orsignificantly alleviates the pain for a number of weeks. It is believedthe basis for this treatment is that the nerve fibers necessary orresponsible for the pain sensation (C fibers) are desensitized by thecapsaicin (or capsaicin analog) and degenerate. However, this effectonly occurs when the active compound concentration in the C fibers ishigh enough. Conventional topical preparations containing capsaicin donot optimally fulfill these requirements, as they release too littlecapsaicin on the skin and the active compound concentration in the Cfibers remains below the effective concentration.

U.S. Pat. No. 6,239,180 (Robbins) describes the use of therapeuticpatches comprising capsaicin and/or a capsaicin analog at aconcentration of greater than 5% to 10% by weight for treatment ofneuropathic pain. The object was thus to develop a patch which issuitable and optimized for the topical therapy of neuropathic pain andother conditions.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1-3 are diagrams showing construction of a microreservoir system.

DETAILED DESCRIPTION

The invention relates to a drug delivery device suitable foradministrating capsaicin, a capsaicin analog, or a mixture thereof. Forconvenience, the term “therapeutic compound” is sometimes used hereinbelow to refer to capsaicin, capsaicin analog(s), or mixtures to beadministered. In one aspect, the invention provides a drug deliverydevice comprising a therapeutic compound-impermeable backing layer, aself-adhesive matrix (usually a polysiloxane-based matrix) comprisingindividual isolated liquid microreservoir droplets (“microreservoirs”)containing capsaicin or a capsaicin analog dissolved in an amphiphilicsolvent, and a protective film to be removed before use of the device.The term “microreservoir system” used herein refers to the saidself-adhesive matrix comprising a plurality of the said microreservoirdroplets which are microdispersed in the matrix. The active compound(e.g., capsaicin) in the microreservoir droplets is dissolved at aconcentration below the saturation concentration (and is thus present incompletely dissolved form).

In a related aspect, the invention provides a method of treatingneuropathic pain in a subject (e.g., human, non-human, primate, ormammal) in need of such treatment by applying a device of the invention.

In another related aspect, the invention provides a method of making adrug delivery device suitable for treatment of neuropathic pain.

A brief discussion of the architecture of therapeutic patches will aidin the appreciation of the present invention. Various forms of topicaland transdermal patches are known for delivering an active compound(e.g., drug), the most common being “matrix systems” and “reservoirsystems”.

Matrix systems are characterized (in the simplest case) by a backinglayer impermeable to the active compound (i.e., compound to be deliveredto the subject), an active compound-containing layer and a protectivelayer to be removed before use. The active compound-containing layercontains the active compound completely or partially in dissolved formand is ideally self-adhesive. In more complicated embodiments, thematrix is composed of a number of layers and can include a controlmembrane. Suitable base polymers for a self-adhesive matrix are, forexample, polyacrylates, polysiloxanes, polyurethanes orpolyisobutylenes.

Reservoir systems are a type of pouch consisting of an impermeable andinert backing layer and an active compound-permeable membrane, theactive compound being present in a liquid preparation in the pouch. Themembrane can be a microporous film or a nonporous partition membrane.Usually, the membrane is provided with an adhesive layer that serves toadhere the system to the skin. The side facing the skin is alsoprotected in this patch design by a film that has to be removed beforeuse.

An advantage of the reservoir systems is that the saturation solubilityof the active compound can be adjusted easily to the particular need bythe choice of the solvent or solvent mixture. For thermodynamic reasons,it is advantageous for the release of active compound in and on the skinif the active compound is present in the active compound-containingparts of the patch at a concentration that is not too far below thesaturation concentration. The uptake capacity of the patch for theamount of active compound needed can be adjusted in a wide range to fitthe particular needs by means of adjusting the amount of active compoundsolution.

In matrix patches, the active compound is included in the adhesivematrix in a form that is safe from leaking, and the patch can be cut tothe size using ordinary scissors. On the other hand, it is difficultunder certain circumstances to adjust the solubility properties of thematrix for the active compound such that the active compound can bedissolved in the matrix in the necessary amount and also remainsdissolved during the storage. In the case of a patch to delivercapsaicin or an analog, the therapeutic compound present in the matrixin undissolved form, or which recrystallizes during the storage period,makes no contribution to the release of active compound in the skinbecause the usual application period for treatment of neuropathic painis short (usually of at most a few hours).

Surprisingly, it has now been found that, for a patch for a highconcentration therapy for the treatment of neuropathic pain withcapsaicin or capsaicin analog, a further, lesser known patch variant, a“microreservoir system”, is particularly highly suitable.

The invention therefore relates to a topical patch comprising atherapeutic compound-impermeable backing layer, a polysiloxane-basedself-adhesive matrix containing at least 1% by weight, preferably atleast 2% by weight, more preferably at least 3% by weight, mostpreferably at least 5% by weight, of capsaicin or capsaicin analog, anda protective film to be removed before use, in which

-   -   a. the matrix contains liquid microreservoirs based on an        amphiphilic solvent, in which the therapeutic compound is        dissolved and    -   b. the concentration of the therapeutic compound in the        microreservoir system is between 20 and 90%, preferably 40 and        70%, of the saturation concentration.

In one embodiment, the therapeutic compound is capsaicin.

Suitable amphiphilic solvents include butanediols, such as1,3-butanediol, dipropylene glycol, tetrahydrofurfuryl alcohol,diethylene glycol dimethyl ether, diethylene glycol monoethyl ether,diethylene glycol monobutyl ether, propylene glycol, dipropylene glycol,carboxylic acid esters of tri- and diethylene glycol, polyethoxylatedfatty alcohols of 6-18 C atoms or2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (Solketal®) or mixtures ofthese solvent. Dipropylene glycol, 1,3-butanediol, diethylene glycolmonoethyl ether (DGME) or 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane ormixtures of these solvents are particularly suitable.

The solvent or the solvent mixture of the microreservoir system cancontain a viscosity-increasing additive. Exemplary viscosity-increasingadditives include a cellulose derivative (e.g., ethylcellulose orhydroxypropylcellulose) and a high molecular weight polyacrylic acid orits salt and/or derivatives such as esters.

The proportion of the microreservoir droplets in the matrix is usuallyless than about 40% by weight, more often less than about 35% by weightand most often between about 20 and about 30% by weight.

Amine-resistant polysiloxanes can be used in the matrix. Preferably, amixture of a polysiloxane of medium tack and a polysiloxane of high tackis used. The used polysiloxanes are synthesized from linear bifunctionaland branched polyfunctional oligomers. The ratio of both types ofoligomers determines the physical properties of the adhesives. Morepolyfunctional oligomers result in a more cross-linked adhesive with ahigher cohesion and a reduced tack, less polyfunctional oligomers resultin a higher tack and a reduced cohesion. The high tack version used inthe examples is tacky enough to stick on human skin. The medium tackversion is nearly not tacky at all but is useful to compensate thesoftening effect of other ingredients like e.g. in this case ofcapsaicin and the solvent of the microreservoirs. To increase theadhesive power of the matrix, this can contain 0.5-5% by weight of asilicone oil (e.g., dimethicone).

In a preferred embodiment of a topical patch according to the invention,the matrix contains at least 5% to about 10% by weight of capsaicin orcapsaicin analog, 10-25% by weight of diethylene glycol monoethyl ether,0-2% by weight of ethylcellulose, 0-5% by weight of silicone oil and58-85% by weight of self-adhesive pressure sensitive polysiloxane. Thecoating weight of the matrix is usually between 30 and 200 g/m²,preferably between 50 and 120 g/m². Suitable materials for the backinglayer include, for example, a polyester film (e.g., 10-20 μm thick), anethylene-vinyl acetate copolymer, and the like.

Suitable capsaicin analogs for use in the patches of the inventioninclude naturally occurring and synthetic capsaicin derivatives andanalogs (“capsaicinoids”) such as, for example, those described in U.S.Pat. No. 5,762,963, which is incorporated herein by reference.

In microreservoir systems, a liquid active compound preparation isdispersed in an adhesive matrix in the form of small droplets(“microreservoirs”). The appearance of a microreservoir system issimilar to a classical matrix system, and a microreservoir system canonly be recognized from a typical matrix system with difficulty, sincethe small microreservoirs can only be recognized under the microscope.In the preceding and the following sections therefore, the activecompound-containing part of the patch is also described by “matrix”. Thesize of the resulting droplets depends on the stirring conditions andthe applied shear forces during stirring. The size is very consistentand reproducable using the same mixing conditions.

It is, however, to be noted that unlike classical matrix systems, inmicroreservoir systems the active compound is dissolved mainly in themicroreservoirs (and only to a small extent in the polymer). In thissense, microreservoir systems can be considered a mixed type of matrixpatch and reservoir patch and combines the advantages of both patchvariants. As in classical reservoir systems, the saturation solubilitycan easily be adjusted by the choice of the solvent to a valve adequatefor the particular requirements, and as in classical matrix systems thepatch can be divided into smaller patches using scissors withoutleakage.

Microreservoir systems can also include a control membrane controllingthe release of active compound and excipient. However, for the specificapplication in the present case (i.e., having a short application timein which is as rapid release of active compound is desired) a controlmembrane usually not present.

Microreservoirs systems are disclosed in U.S. Pat. Nos. 3,946,106,4,053,580, 4,814,184 and 5,145,682, each of which is incorporated hereinby reference. Specific microreservoirs systems are described ininternational patent publication WO-A-01/01,967 the disclosure of whichis incorporated herein by reference. These microreservoir systemscontain, as base polymer, polysiloxanes and amphiphilic solvents for themicroreservoir droplets. It has now been discovered that suchmicroreservoir systems are particularly highly suitable, on the basis ofthe good solubility of capsaicin and capsaicin analogs in amphiphilicsolvents such as, for example, diethylene glycol monoethyl ether,1,3-butanediol, dipropylene glycol and Solketal, for a topical highconcentration therapy using these active compounds.

A particularly highly suitable solvent has proven to be diethyleneglycol monoethyl ether (DGME, also known by the trade name Transcutol®).The solubility of capsaicin in DGME is about 50% by weight, and thesolubilities of capsaicin analogs structurally similar to capsaicin arecomparable. This means that in order to incorporate enough activecompound into the matrix, the therapeutic compound does not necessarilyhave to dissolve in DGME in a concentration near the saturation limit.The result is that the patch itself is not amenable to recrystallizationof the therapeutic compound (e.g., capsaicin) even under unfavorableconditions, such as, for example, the partial loss of the solvent or lowtemperature. In practice, an about 20-35% by weight solution ofcapsaicin in DGME has proven particularly highly suitable. Because thesaturation concentration of capsaicin in DGME is 50% by weight, thissolution is 40-70% by weight of the saturation solubility. In thiscontext, the concentration is calculated according to the followingformula:

Weight of therapeutic compound×100/(weight of therapeuticcompound+weight of solvent)

An advantage of using DGME is that, in addition to the high saturationlimit of capsaicin in this compound, DGME acts as a penetrationenhancer. It is therefore advantageous that after application of thepatch to the skin, DGME is released along with the capsaicin or analog.The simultaneous release of DGME causes the concentration, and thus alsothe thermodynamic activity of the therapeutic compound in themicroreservoir system, to remain at a high level despite release. As theresults of permeation experiments on human epidermis shown in Table 2demonstrate, the active compound flux from such systems is approximatelytwice as high as that from a matrix which is supersaturated withcrystalline capsaicin. This is an indication that the active compoundconcentration in the microreservoir system increases even above thesaturation solubility and the system even becomes supersaturated withdissolved capsaicin. Because of the short application time, thetherapeutic compound, however, has no opportunity to recrystallize, suchthat the active compound flux into the skin or the active compounddispersion into the skin is very effective. The rapid increase of theconcentration of the active compound in the active compound reservoirsdue to the fast release of DGME after the application of the patch isthe final reason why the initial concentration of the active compoundcan be well below the saturation concentration without that the activecompound flux is adversely affected. The absorption of moisture from theskin makes a further contribution. Because of the extremely lowabsorption capacity of polysiloxanes for water, moisture can onlymigrate into the microreservoirs. Water is a very poor solvent forcapsaicin and most capsaicin analogs. As a result, the saturationconcentration of the therapeutic compound in the microreservoirs islowered and thus its thermodynamic activity of the therapeutic compoundis increased.

In order that these mechanisms can be effective, it is important thatdiffusible substances in the polymer have a high diffusion coefficient.For this reason, polysiloxanes as base polymers are preferred to allother polymers now in use for microreservoir systems.

Polysiloxanes can be made from solvent-free two-component systems or asolution in organic solvents. For patch production, self-adhesivepolysiloxanes dissolved in solvents are preferred.

These exist in two fundamentally different variants of polysiloxanes:the normal polysiloxane which have free silanol groups as shown informula I,

and the “amine-resistant variants”, which are distinguished in that thefree silanol groups are derivatized by trimethylsilyl groups. Suchamine-resistant polysiloxanes have also proven suitable for therapeuticcompound-containing patches without active compound and/or excipientswhich both do not have a basic group. Owing to the absence of freesilanol groups, the solubility of active compounds in the polymer isfurther reduced and the diffusion coefficient is further increased formany therapeutic compounds due to the interaction with the polar freesilanol groups, which is not possible. Formula I shows the structure ofa linear polysiloxane molecule that is prepared from dimethylsiloxane bypolycondensation. Three-dimensional crosslinking can be achieved by theadditional use of methylsiloxane.

In further polysiloxanes according to the invention, the methyl groupscan be completely or partially replaced by other alkyl radicals oralternatively phenyl radicals.

Without the invention being restricted thereto, the fundamental matrixcomposition of an embodiment of a patch according to the inventioncontaining the therapeutic compound capsaicin can be seen from Table 1below.

TABLE 1 Composition of the matrix of a microreservoir system for thetopical high-dose therapy of capsaicin Component Percent by weightCapsaicin 8 Transcutol ® (DGME) 20 Self-adhesive polysiloxane 72 matrix

The thickness of the matrix is generally between about 30 and about 200μm (corresponding to a coating weight of about 30 to about 200 g/m²),but values differing therefrom can also be used depending on theproperties of the specific formulation. In practice, a matrix thicknessof between 50 and 100 μm has proven particularly highly suitable.

The backing layer for the patch should ideally be as impermeable orinert as possible for the therapeutic compound and DGME or theamphiphilic solvent selected. Polyester fulfills this condition, butother materials such as, for example, ethylene-vinyl acetate copolymersand polyamide are suitable. In practice, a polyester film about 20 μmthick has proven highly suitable. In order to improve the adhesion ofthe matrix to the backing layer, it is advantageous to siliconize thecontact side of the backing layer to the matrix. Adhesives based onpolyacrylates do not adhere to such siliconized films or only adherevery poorly, adhesives based on polysiloxanes, however, adhere very wellon account of the chemical similarity.

As the protective film to be removed before use, a polyester film isbest used which due to a specific surface treatment is repellent toadhesives based on polysiloxanes. Suitable films are supplied by anumber of manufacturers and are known best to the person skilled in theart.

The self-adhesive polysiloxane matrix can be a mixture of adhesiveshaving different adhesive behavior in order to optimize the adhesivebehavior of the patch to the skin. For further improvement of theadhesive behavior, a silicone oil of suitable viscosity or molecularweight can additionally be added in a concentration of up to about 5% byweight.

The invention also relates to a process for the production of a topicalpatch according to the invention, which comprises dissolving thetherapeutic compound in an amphiphilic solvent, adding this solution toa solution of a polysiloxane or the matrix constituents and dispersingwith stirring, coating the resulting dispersion onto a protective layerwhich is removable and removing the solvent of the polysiloxane atelevated temperature and laminating the backing layer onto the driedlayer.

The solvent for the therapeutic compound must not mix or may only mix toa small extent with the solvent for the adhesive. Suitable solvents foradhesives are, for example, petroleum ethers or alkanes such as n-hexaneand n-heptane. It has been shown that the dispersion of the therapeuticcompound solution can be realized more easily if the viscosity of thetherapeutic compound solution is increased by the addition of a suitableagent such as, for example, a cellulose derivative such asethylcellulose or hydroxypropylcellulose. The dispersion is now coatedonto the removable protective film in a thickness, which after theremoval of the solvent of the adhesive, affords a matrix layer havingthe desired thickness. The dried layer is now laminated with the backinglayer and thus the finished patch laminate is obtained.

The patches can now be punched out of this laminate in the desired shapeand size and packed into a suitable sachet of primary packing. A highlysuitable primary packing has proven to be a laminate consisting ofpaper/glue/aluminum foil/glue/Barex®, as is described in U.S. Pat. No.RE37,934. Barex® is a heat-sealable polymer based on rubber-modifiedacrylonitrile copolymer, which is distinguished by a low absorptivityfor volatile ingredients of patches.

The aim of the invention was the development of a patch having anoptimized therapeutic compound flux into the human skin. Because themicroreservoir system within the meaning of this invention has nomembrane controlling the release of therapeutic compound, and also thematrix itself can exert no kinetic control on the release of therapeuticcompound due to the high diffusion coefficient of the therapeuticcompound in polysiloxanes, the only element controlling the release oftherapeutic compound into the deeper skin layers is the skin or theuppermost layer of skin or the uppermost layer of skin, the stratumcorneum. The optimization of the matrix composition was thereforeconsistently carried out by in vitro permeation studies using human skinand by Franz diffusion cells known to the person skilled in the art forthe experimental procedure.

In a first study, the influence of DGME on the permeation rate wasinvestigated. The results are shown in Table 2.

TABLE 2 Influence of DGME on the permeation rate of capsaicin throughhuman epidermis ⁽¹⁾ Cumulated amount of Permea- capsaicin [μg/cm²] ⁽²⁾after tion rate Formulation 1 h 2 h 3 h 4 h 6 h 8 h [μg/cm² * h]Formulation 0.72 2.37 4.24 5.93 9.37 12.70 1.59 1 ⁽³⁾ (with DGME)Formulation 0.34 1.09 1.96 2.79 4.52 6.32 0.79 2 ⁽⁴⁾ (without DGME) ⁽¹⁾Epidermis, female breast, age 37 years ⁽²⁾ Mean values from 3 individualmeasurements each ⁽³⁾ 8% by weight of capsaicin and 21% by weight ofDGME in amine-resistant polysiloxane matrix ⁽⁴⁾ Matrix supersaturatedwith crystalline capsaicin

In formulation 2, the therapeutic compound capsaicin is largely (>95% byweight) dispersed in the matrix undissolved in the form of smallcrystals. This means that the matrix is saturated with dissolvedcapsaicin and the thermodynamic activity of the therapeutic compound ismaximal for a stable matrix which is not supersaturated. Formulation 1shows a permeation rate that is approximately twice as high.

Ignoring the small amounts of capsaicin that are dissolved in thepolysiloxane itself, the concentration of the capsaicin in themicroreservoir droplets in formulation 1 is about 28% by weight. This isconsiderably below the saturation solubility of 50% by weight andguarantees that even in the case of a partial loss of the DGME or atreduced temperature there is no danger of recrystallization in thematrix. This means that before use the patch is physically stable andreaches a higher saturated or supersaturated state associated with agreatly increased permeation rate only after application.

In a second series, the influence of the capsaicin concentration on thepermeation rate was investigated. The results are shown in Table 3.

TABLE 3 Influence of the capsaicin concentration on the permeation ratethrough human epidermis ⁽¹⁾ Cumulated amount of Permea- capsaicin [μg/cm²] ⁽²⁾ after tion rate Formulation ⁽³⁾ 1 h 2 h 3 h 4 h 6 h 8 h[μg/cm² * h] Formulation 0.32 0.69 1.0 1.44 2.15 2.98 0.37 3 4% byweight of capsaicin Formulation 0.30 0.74 1.40 1.71 2.77 3.93 0.49 4 6%by weight of capsaicin Formulation 0.54 1.02 1.72 2.37 3.44 4.64 0.58 58% by weight of capsaicin ⁽¹⁾ Epidermis, female breast, age 47 years ⁽²⁾Mean values from 3 individual measurements ⁽³⁾ DGME concentration 21% byweight

The permeation rate shows a marked dependence on the capsaicinconcentration, i.e. the release rate of the patch can be adjusted easilyto the value necessary for capsaicin or capsaicin analog via theconcentration in DGME (or the solvent intended for the microreservoirs).

A capsaicin concentration of about 8% by weight (e.g., about 5% to about10% by weight, usually 7% to 9% by weight) in combination with a DGMEconcentration of about 15% to about 25% by weight has provenparticularly highly suitable.

A therapeutic compound-containing matrix optimized with respect to theadhesive behavior on the skin and the other physical properties has thefollowing composition:

TABLE 4 Optimized composition of the matrix of a microreservoir systemfor topical high-dose therapy using capsaicin Component Percent byweight capsaicin 8 DGME 20 Ethylcellulose 0.8 High-tack amine-resistant21 polysiloxane BIO-PSA 4301, Dow Corning Medium-tack amine-resistant 49polysiloxane BIO-PSA 4201, Dow Corning Silicone oil, 12,500 cSt 2Coating weight 80 g/m²

Patches within the meaning of this invention containing the therapeuticcompound capsaicin have proven very effective in appropriate clinicalstudies. Even a one-hour treatment of the affected areas reduced thesensation of pain significantly, the action lasting for weeks. Thepatches in this case proved to be highly tolerable and were very wellaccepted by the patients. In summary, it can thus be said that patcheswithin the meaning of this invention are optimally suitable fortreatment of neuropathic pain described in U.S. Pat. No. 6,248,788 usinghigh concentration of capsaicin or capsaicin analogs.

The invention therefore also relates to use of a topical patch accordingto the invention for the treatment of neuropathic pain and otherconditions.

Use of the Capsaicin or Capsaicin Analog Patch

This section describes use of the invention. However, it will beunderstood that the examples in this section are provided forillustration and not limitation. Capsaicin application has numeroustherapeutic benefits, each of which can be effectively treated using themethods of the invention. Conditions for which capsaicin or capsaicinanalog treatment may be indicated include neuropathic pain (includingpain associated with diabetic neuropathy, postherpetic neuralgia,HIV/AIDS, traumatic injury, complex regional pain syndrome, trigeminalneuralgia, erythromelalgia and phantom pain), pain produced by mixednociceptive and/or neuropathic mixed etiologies (e.g., cancer,osteoarthritis, fibromyalgia and low back pain), inflammatoryhyperalgesia, interstitial cystitis, dermatitis, pruritis, itch,psoriasis, warts, and headaches. Generally, the capsaicin- or capsaicinanalog-containing patches can be used to treat any condition for whichtopical administration of capsaicin is beneficial.

EXAMPLES

The following examples serve to illustrate the invention without thelatter having to be restricted thereto.

Example 1 Production of a Patch Containing Capsaicin

250 g of DGME are initially thickened with 4.5 g of ethylcellulose withstirring. 97 g of capsaicin is then added and completely dissolved withstirring. 286 g of the above therapeutic compound solution is added to1000 g of a solution of the polysiloxane or the mixture of thepolysiloxanes in n-heptane having a solids content of 70% by weight anddispersed in the adhesive solution with intensive stirring.

Subsequently, using a suitable coating process, the dispersion is coatedonto a removable protective film and is suitable for polysiloxaneadhesives, e.g. Scotchpak® 1022 from 3M, in a thickness such that thecoating weight after the removal of the n-heptane is 80 g/m². The driedfilm is then laminated with the backing layer, e.g. polyester film 20 μmthick, and the finished patch is punched out of the complete laminate.The punched patches are then sealed into a sachet of a suitable primarypacking laminate.

The temperatures under which the solvent of the adhesive, n-heptane, isremoved, should ideally not exceed 40° C. There is more DGME in thefinal bulk mixture than in the final composition due to loss of DGMEduring the drying process.

Example 2

196 g of DGME is initially thickened with 4 g of ethylcellulose withstirring. 30 g of nonivamide (pelargonic acid vanillylamide) are thenadded and completely dissolved with stirring.

The solution is then added to 1000 g of a solution of the polysiloxaneor the mixture of the polysiloxanes in n-heptane having a solids contentof 70% by weight and dispersed in the adhesive solution with intensivestirring.

Subsequently, using a suitable coating process, the dispersion is coatedonto a removable protective film, e.g. Scotchpak® 1022 from 3M, in athickness such that the coating weight after the removal of then-heptane is 100 g/m². The dried film is then laminated with the backinglayer, e.g. polyester film 20 μm thick, and the finished patch ispunched out of the complete laminate. The punched patches are thensealed into a sachet of a suitable primary packaging.

Example 3

200 g of dipropyleneglycol are thickened with 2 g ofhydroxyethylcellulose with stirring. 60 g of capsaicin is then added andcompletely dissolved with stirring.

The solution is then added to 1000 g of a solution of the polysiloxaneor the mixture of the polysiloxanes in n-heptane having a solids contentof 70% by weight and dispersed in the adhesive solution with intensivestirring.

Subsequently, using a suitable coating process, the dispersion is coatedonto a removable protective film, e.g. Scotchpak® 1022 from 3M, in athickness such that the coating weight after the removal of then-heptane is 100 g/m². The dried film is then laminated with the backinglayer, e.g. polyester film 20 μm thick, and the finished patch ispunched out of the complete laminate. The punched patches are thensealed into a sachet of a suitable primary packaging.

Example 4

Same procedure as described in example 1 but olvanil (oleylvanillylamide) is used instead of capsaicin.

Example 5

36 g of nonivamide is dissolved in 164 g of Solketal with stirring. Thesolution is then added to 1000 g of a solution of the polysiloxane orthe mixture of the polysiloxanes in n-heptane having a solids content of70% by weight and dispersed in the adhesive solution with intensivestirring.

Subsequently, using a suitable coating process, the dispersion is coatedonto a removable protective film, e.g. Scotchpak® 1022 from 3M, in athickness such that the coating weight after the removal of then-heptane is 100 g/m². The dried film is then laminated with the backinglayer, e.g. polyester film 20 μm thick, and the finished patch ispunched out of the complete laminate. The punched patches are thensealed into a sachet of a suitable primary packaging.

1. A topical patch comprising a therapeutic compound-impermeable backinglayer, a self-adhesive matrix based on polysiloxanes containing at least1% by weight, preferably at least 2% by weight, more preferably at least3% by weight, most preferably at least 5% by weight, of the therapeuticcompound, and a protective film to be removed before use, in which a.the matrix contains liquid microreservoir droplets comprising anamphiphilic solvent, in which the therapeutic compound is dissolved, andb. the concentration of the therapeutic compound in the microreservoirdroplets is between 20 and 90% by weight of the saturation concentrationwherein the therapeutic compound is capsaicin or a capsaicin analog or amixture thereof.
 2. The topical patch as claimed in claim 1, in whichthe therapeutic compound is capsaicin.
 3. The topical patch as claimedin claim 1, in which the concentration in the therapeutic compound inthe microreservoir droplets is between 40 and 70% by weight of thesaturation concentration.
 4. The topical patch as claimed in claim 1, inwhich the amphiphilic solvent is a butanediol, such as 1,3-butanediol,dipropylene glycol, tetrahydrofurfuryl alcohol, diethylene glycoldimethyl ether, diethylene glycol monoethyl ether, diethylene glycolmonobutyl ether, propylene glycol, dipropylene glycol, carboxylic acidesters of tri- and diethylene glycol, polyethoxylated fatty alcohols of6-18 C atoms or 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, or mixturesof these solvents.
 5. The topical patch of claim 4 wherein the solventis diethylene glycol monoethyl ether.
 6. The topical patch as claimed inclaim 1, in which the microreservoir droplets comprise aviscosity-increasing additive dissolved in the solvent.
 7. The topicalpatch as claimed in claim 6, in which the viscosity-increasing additiveis a cellulose derivative or a high molecular weight polyacrylic acid.8. The topical patch of claim 7, in which the viscosity-increasingadditive is ethylcellulose or hydropropylcellulose.
 9. The topical patchas claimed in claim 1, in which the proportion of the microreservoirdroplets in the matrix is less than 40% by weight, preferably less than35% by weight, in particular between 20 and 30% by weight.
 10. Thetopical patch as claimed in claim 1, in which the self-adhesive matrixcomprises an amine-resistant polysiloxane.
 11. The topical patch asclaimed in claim 10, in which the self-adhesive matrix comprises amixture of a polysiloxane of medium tack and a polysiloxane of hightack.
 12. The topical patch as claimed in claim 10, wherein the matrixcontains from about 0.5 to about 5% by weight of a silicone oil.
 13. Thetopical patch as claimed in claim 1, in which the matrix comprises 5-10%by weight of capsaicin or a capsaicin analog, 10-25% by weight ofdiethylene glycol monoethyl ether, 0-2% by weight of ethylcellulose,0-5% by weight of silicone oil, and 58-85% by weight of self-adhesivepolysiloxane and the coating weight of the matrix is between 30 and 200g/m², preferably between 50 and 120 g/m².
 14. The topical patch asclaimed in claim 1, in which the matrix consists essentially of 5-10% byweight of capsaicin or a capsaicin analog, 10-25% by weight ofdiethylene glycol monoethyl ether, 0-2% by weight of ethylcellulose,0-5% by weight of silicone oil, and 58-85% by weight of self-adhesivepolysiloxane and the coating weight of the matrix is between 30 and 200g/m², preferably between 50 and 120 g/m².
 15. The patch as claimed inclaims 1 to 14, in which the backing layer consists of a polyester film10-20 μm thick.
 16. The topical patch as claimed in claim 1, in whichthe backing layer consists of an ethylene-vinyl acetate copolymer. 17.The use of a topical patch as claimed in claim 1 for the treatment ofneuropathic pain.
 18. The topical patch as claimed in claim 1 for use inthe treatment of neuropathic pain.
 19. A method for the treatment ofneuropathic pain, in which a topical patch as claimed in claim 1containing an amount of capsaicin or capsaicin analog effective for thisuse is applied.
 20. A method for the production of a topical patch asclaimed in claim 1, which comprises dissolving the therapeutic compoundin an amphiphilic solvent, adding this solution to a solution of apolysiloxane or the matrix constituents and dispersing, coating theresulting dispersion onto a protective layer which is removable againand removing the solvent of the polysiloxane and laminating the backinglayer onto the dried matrix layer.